The present invention relates to a novel method for the preparation of chiral [1,4]diazepino[6,7,1-hi]-indol-4-ones of use in the preparation of medicaments which make possible the treatment of ailments involving therapy by an inhibitor of phosphodiesterases 4 (PDE4). These medicaments are of use in particular as antiinflammatories, antiallergics, bronchodilators or antiasthmatics.
The international patent application published under No. WO 98/49169, the contents of which are incorporated in the present application by reference, discloses diazepino-indolones, which are compounds active as inhibitors of PDE4 enzymes, of formula 
in which:
A is hydrogen, lower alkyl, lower alkoxy, nitro or amino;
B is hydrogen or optionally functionalized lower alkyl;
X1 and X2, which are alike or different, can be hydrogen, halogen, lower alkyl, lower alkoxy or alternatively xe2x80x94CH2OH or xe2x80x94CO2H, which are optionally substituted;
Z is CH, then Z1 and Z2 are both CH or N; or Z is N, then Z1 and Z2 are CH.
In this Application WO 98/49169, the preferred diazepino-indolones of formula (I) are those in which the 3 carbon of the [1,4]diazepino[6,7,1-hi]indol-4-one nucleus has the S configuration.
These compounds were obtained in Patent Application WO 98/49169 as racemic compounds and could only be separated by chiral phase chromatography or else by the formation of salts with an enantiomerically pure amine. The synthetic process disclosed in Patent Application WO 98/49169 can exhibit disadvantages, including, on occasions, low yields and the need for a resolution stage.
In point of fact, an improved process has now been found for the preparation of these same products directly in the form of pure enantiomers, which process is efficient and economic and forms the subject-matter of the present invention. Consequently, the present process avoids the disadvantages of the known processes and it can be adapted to a larger scale.
The invention relates to an improved process for the preparation of chiral substituted [1,4]diazepino[6,7,1-hi]indol-4-ones of formula (I) 
in which, in particular:
A is hydrogen, lower alkyl, lower alkoxy, nitro or amino;
B is hydrogen or lower alkyl;
Z is CH, then Z1 and Z2 are together CH or N; or Z is N, then Z1 and Z2 are CH;
X1 and X2, which are alike or different, can be hydrogen, halogen, lower alkyl, lower alkoxy or alternatively xe2x80x94CH2OH or xe2x80x94CO2 H, which are optionally substituted.
The invention is targeted at a process for the preparation of the enantiomers of the diazepino-indolones (I) of formula 
in which:
A is hydrogen, lower alkyl, hydroxyl, lower alkoxy, nitro, cyano or NR1R2; R1 and R2 are independently hydrogen or lower alkyl or form, together with the nitrogen atom to which they are bonded, a ring having 4 or 5 carbon atoms;
B is hydrogen or lower alkyl;
Z is CH, then Z1 and Z2 are together CH or N; or Z is N, then Z1 and Z2 are CH;
X1 and X2 are independently hydrogen, C1-C4 alkyl, xe2x80x94(CH2)jxe2x80x94OR3, halogen, cyano, xe2x80x94Oxe2x80x94(C1-C6 alkyl), xe2x80x94C(xe2x95x90O)R4, xe2x80x94C(xe2x95x90O)OR5, xe2x80x94C(xe2x95x90O)NR6R7, or 
R3, R4 and R5 are independently hydrogen, C1-C6 alkyl, benzyl, phenethyl or xe2x80x94Q1xe2x80x94Q2;
R6 is hydrogen or C1-C4 alkyl;
R7 is hydrogen, C1-C4 alkyl, xe2x80x94CHRAxe2x80x94C(xe2x95x90O)OM2 or xe2x80x94Q3xe2x80x94Q4;
R8 is hydrogen, C1-C4 alkyl or xe2x80x94Q5xe2x80x94Q6;
RA is a natural xcex1-amino acid residue, the carbon atom to which it bonded being able to have either the S configuration or the R configuration;
Q1 is xe2x80x94(CH2)kxe2x80x94(CHOH)mxe2x80x94(CH2)pxe2x80x94;
Q2 is hydroxyl, xe2x80x94Oxe2x80x94(C1-C6 alkyl), xe2x80x94OC(xe2x95x90O)xe2x80x94(C1-C6 alkyl) or 4-morpholinyl;
Q3 and Q5 are independently a bond, xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94 or xe2x80x94(CH2)3xe2x80x94;
Q4 is xe2x80x94NM3M4 or 4-morpholinyl;
Q6 is xe2x80x94M5 or xe2x80x94OM6;
M1, M2, M3, M4, M5 and M6 are independently hydrogen or C1-C4 alkyl;
j is 1, 2 or 3; k is 1, 2 or 3;
m is 0, 1, 2, 3 or 4; p is 0, 1, 2 or 3, with the proviso that, if m greater than 0, then p greater than 0;
their isomers, their racemic forms, as well as their salts, solvates, esters, amides and prodrugs which are pharmaceutically acceptable.
In what precedes and in what follows:
the term xe2x80x9chalogenxe2x80x9d is understood to mean fluorine, chlorine, bromine or iodine;
the term xe2x80x9clower alkylxe2x80x9d or xe2x80x9cC1-C4 alkylxe2x80x9d is understood to mean a linear or branched radical comprising from 1 to 4 carbon atoms or alternatively the cyclopropylmethyl radical;
the term xe2x80x9clower alkoxyxe2x80x9d is understood to mean a radical of formula xe2x80x94O-Alk, where Alk is lower alkyl;
the term xe2x80x9cC1-C6 alkylxe2x80x9d is understood to mean a linear or branched radical comprising from 1 to 6 carbon atoms or alternatively the cyclopropylmethyl radical.
The process of the present invention makes it possible to obtain the chiral [1,4]diazepino[6,7,1-hi]indol-4-ones (I) directly, in the form of pure enantiomers, from optically active 3-aminobenzodiazepines (II) in a stage represented in Scheme 1, 
where A, Z, Z1, Z2, B, X1 and X2 have the meanings defined above for (I);
R is a lower alkyl radical, preferably the methyl radical.
During this reaction, an intermediate (II) is cyclized, preferably at normal temperature or below 0xc2x0 C., in the presence of a Lewis acid, such as scandium trifluoromethanesulphonate, to give the product (I).
The intermediate (II) is dissolved in a solvent and a catalytic amount of Lewis acid, preferably scandium trifluoromethanesulphonate, is added at normal temperature. The product (I) is obtained, the optical purity of which is confirmed by analytical HPLC.
More generally, the Lewis acids of use in the process of the present invention are described in particular in the following publications: i) Advanced Organic Chemistry, Third Edition, by Jerry March (John Wiley and Sons, New York, 1985); ii) xe2x80x9cFriedel-Crafts Reactionsxe2x80x9d, Olah, G. and Meidar, D.; Kirk-Othmer Encyclopedia of Chemical Technology, Third Edition, 11, 269-300 (John Wiley and Sons, New York, 1978), iii) xe2x80x9cQuantitative Aspects of Lewis Acidityxe2x80x9d, Satchell, D. P. N. and Satchell, R. S.; Quarterly Reviews (The Chemical Society, London), 1971, 25: 171-199, iv) xe2x80x9cLanthanide triflates as unique Lewis acidsxe2x80x9d, Xie, W., Jin, Y. and Wang, P. G.; CHEMTECH, 1999, 29, 23-29, and v) Marshman, R. W., xe2x80x9cRare earth triflates in organic synthesisxe2x80x9d, Aldrichimica Acta, 1995, 28, 77-84.
Strong Lewis acids (such as aluminium chloride, ferric chloride and equivalents) do not seem, in the present invention, as effective catalysts as weak Lewis acids.
Examples of Lewis acids of use in the present invention are compounds or complexes of formula:
[LXxYy]
having a vacant orbital,
where L is a metal, boron, silicon or antimony,
X and Y are neutral or anionic, nonmetallic ligands, atoms or radicals,
x and y are each zero or an integer.
Typical values of L comprise boron, aluminium, silicon, scandium, titanium, gallium, indium, yttrium, zirconium, silver, tin, antimony, lanthanum and lanthanides, mercury, thallium, manganese, iron, cobalt, nickel, copper, zinc, calcium and magnesium or another transition metal. Preferred values of L comprise boron, silicon, aluminium, scandium, lanthanides, titanium, gallium, silver, tin, iron, zinc and magnesium.
Typical values of X and Y are chosen from halides, oxygen, oxygen-comprising ligands, organic radicals and organic anions.
The oxygen-comprising ligands comprise, for example, oxygen or alkoxy, phenoxy, carboxylate, xcex2-ketocarboxylate, sulphate, sulphonate, phosphate, phosphonate and equivalent radicals.
The organic radicals comprise, for example, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, phenylalkyl and (substituted phenyl)alkyl radicals.
The organic anions comprise cyclopentadienyl and substituted cyclopentadienyl anions.
The Lewis acids preferably comprise at least one oxygen-comprising ligand, for example an alkoxy radical or a sulphonate radical. The preferred weak Lewis acids are boron, aluminium, silicon, scandium, lanthanide, titanium, gallium, silver, tin, iron, zinc or magnesium complexes comprising at least one oxygen-comprising ligand. Specific examples of weak Lewis acids of use in the present invention are scandium trifluoromethanesulphonate, aluminium trifluoromethane-sulphonate, as well as ytterbium or other lanthanide, silicon, magnesium, tin(II), copper(II), zinc or silver trifluoromethanesulphonates; dimethoxydicyclopenta-dienyltitanium(IV) or dicyclo-pentadienyltitanium(IV) bis(trifluoromethanesulphonate); iron(III), aluminium or zinc acetylacetonate; zinc diacetate; dimethoxymagnesium; triisopropoxyaluminium, tetra-butoxytitanium(IV), tetraisopropoxytitanium(IV), trimethylboron, triethylaluminium, diethylzinc, triisobutylaluminium, tetrabutyltin(IV), triphenyl-boron, triphenylantimony; or halides, in particular zinc, tin(II), antimony(III), antimony(V), titanium(III), titanium(IV), scandium, indium, gallium and mercury(II) chlorides or, preferably, bromides.
The cyclization reaction is carried out in an inert solvent, that is to say a solvent or mixture of solvents which does not react with the reactants or the reaction products and which does not react in an unfavourable way with the Lewis acid catalyst. The solvent is aprotic and preferably not very polar. Representative solvents are: aromatic hydrocarbons, such as benzene, toluene, nitrobenzene or chlorobenzene; aliphatic hydrocarbons, such as pentane, hexane or heptane; dialkyl ethers, such as ethyl or isopropyl ether; chlorinated hydrocarbons, such as dichloromethane, trichloromethane, tetrachloromethane or dichloroethylene; 1,1,1-trimethoxyalkanes, such as trimethyl orthoacetate; cyclic ethers, such as tetrahydrofuran or dioxane; and their mixtures. It is not necessary for the reactants or the catalyst to be completely dissolved in the solvent used.
The amount of Lewis acid used generally represents from 1 to 10 mol equivalent % with respect to the starting material (II). In this cyclization reaction, the minimum amount of Lewis acid relative to the product of formula (II) depends on the activity of the Lewis acid under consideration, on the temperature reaction and on its maximum allotted duration; it is determined by routine experiments. The Lewis acid can advantageously be easily recycled at the end of the reaction.
The Lewis acid catalyst is preferably soluble in the solvent used.
A dehydrating agent, such as anhydrous magnesium sulphate or a molecular sieve, can optionally be introduced into the cyclization reaction mixture.
The cyclization reaction is carried out at a temperature of between approximately 0xc2x0 C. and 40xc2x0 C. and preferably between approximately 25xc2x0 C. and 40xc2x0 C. It is advisable not to exceed 40xc2x0 C. in order not to epimerize the stereogenic centre.
The duration of the reaction is generally between 6 and 48 h. Its progress can be monitored by analytical HPLC or TLC; the reaction is thus stopped after the starting material has disappeared.
When A is a primary amine group in the final product, the process comprises an additional stage where a product (I), in which A is xe2x80x94NO2, is reduced to a product (I), in which A is xe2x80x94NH2, by a chemical or catalytic reduction which respects the asymmetric carbon. This stage consists in specifically reducing a compound (I), in which A is nitro, which reduction is carried out by appropriate reducing systems: these are, inter alia, zinc in acid medium, titanium chloride in acid medium or else tin chloride in ethanolic medium; this stage is represented in the experimental part below by the synthesis of the products 7, 13 and 18.
These reductions are carried out under cold conditions but the preferred reduction is carried out in methanol, with ruthenium-on-charcoal as catalyst, at a temperature not exceeding 80xc2x0 C. and under a hydrogen pressure of 400 to 800 kPa. The hydrogenation time should be less than 2 h and preferably 1.5 h.
The intermediate (II) can be prepared according to the process presented in Scheme 2, where A, Z, Z1, Z2, X1 and X2 have the meanings defined for (I) and PG is a protecting group. 
The first stage consists of the condensation of an optically active aminobenzodiazepine (VI) with a suitably substituted anthranilic acid (V) protected on the amine functional group, in order to obtain an intermediate (IV).
The intermediate (IV) is subsequently deprotected to give the intermediate (III) with a free amine functional group.
The intermediate (III), reacted with an appropriate ortho ester (or 1,1,1-trialkoxyalkane) (VII) under mild conditions, in order not to epimerize the asymmetric carbon of the benzodiazepine, gives an intermediate (II).
In some cases, an anthranilic acid (Vxe2x80x2) which is unprotected on the amine functional group can be condensed directly with the aminobenzodiazepine (VI), which directly provides the intermediate compound (III) (Process B).
More specifically, Process A, as presented in Scheme 2, comprises the preparation of the intermediates (IV) by reaction of an amino intermediate (VI) with an intermediate (V) prepared from a 2-anthranilic acid. It consists, with a protected 2-anthranilic acid (V), in carrying out, in a first stage, the N-acylation of the amine (VI). The operation is carried out in an anhydrous organic solvent, such as a chlorinated hydrocarbon, for example dichloromethane or trichloromethane, a linear or cyclic ether, such as 1,2-dimethoxyethane, tetrahydrofuran or dioxane, a polar aprotic solvent, such as pyridine, dimethyl sulphoxide or N,N-dimethylformamide (DMF), or any other suitable solvent and their mixtures. The reaction is advantageously carried out in the presence of a coupling agent and optionally of an organic base.
Thus, use is made, as coupling agent, of:
an O-[(ethoxycarbonyl)cyanomethylamino]-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium tetrafluoroborate/N,N-diisopropylethylamine combination, or
an isobutyl chloroformate/N-methylmorpholine combination, or
preferably, a combination of hydroxybenzotriazole (HOBT) and of a carbodiimide, such as N,Nxe2x80x2-dicyclohexylcarbodiimide (DCC), which is the preferred reagent, N,Nxe2x80x2-disopropylcarbodiimide or carbonyldiimidazole, in a neutral anhydrous solvent, such as dichloromethane or DMF, at 0xc2x0 C.
In this first stage of Process A, the t-butoxycarbonylamino acid (V) is used in the isolated form.
The second stage consists in deprotecting the amine functional group of the intermediate (IV), in order to obtain the primary amine (III). With this aim, the intermediate (IV) can be dissolved in an acid, such as trifluoroacetic acid, which is the preferred process, and left to react for a time which depends on the nature of the protecting group employed. In the case of the preferred protecting group PG, which is the t-butoxycarbonyl group, hereinafter xe2x80x9ct-BOCxe2x80x9d, the products are left in contact for half an hour and the mixture is evaporated. The product is taken up in dichloromethane and neutralized with a 5% aqueous NaHCO3 solution.
The intermediate (III) is obtained.
In the experimental part which illustrates the invention, Examples 1, 2, 4 and 5 are representative of Process A.
The intermediate (III) can also be obtained, with a possibly lower yield, by direct coupling of an anthranilic acid which is unprotected on the amine functional group (Vxe2x80x2) with the starting enantiomeric amine (VI) by Process B.
In this case, the coupling agent can also be the DCC/HOBT combination. Use may be made, for this stage, of other acids, such as formic acid, dichloroacetic acid or any other organic or inorganic acid, mixed or not with a solvent in various proportions, at a concentration and at a temperature such that there is no hydrolysis of the benzodiazepine nucleus.
In the experimental part, Example 3 is representative of Process B. 
Starting from the intermediate (III), the following stages are common to both processes.
In the third stage, a solution of the intermediate (III) is stirred with an ortho ester (VII), preferably a methyl ortho ester, in order to obtain the intermediate (II), which is not purified but is employed as is in the following stage. During this third stage, it is advisable to remain at low temperature and in particular not to exceed 40xc2x0 C., failing which (III) and (II) would epimerize to give a racemic mixture. The duration of the coupling can reach 24 h but it is sometimes much faster. It is possible, by vacuum distillation, to remove the methanol which has formed during the reaction; the reaction is thus complete.
The protected and substituted anthranilic acids (V) are described in the literature; if not, they are prepared in a way analogous to the preparation of 2-(t-butoxycarbonylamino)benzoic acid 2, which preparation is described in the experimental part below.